Cancer cells excessively express tumor-associated antigens. The host immune system is considered to respond to the tumor-associated antigens and then exert cellular immunity to eliminate tumors. However, various immune escape mechanisms are present in microenvironment, such as tumor, or in the whole body, and when hosts fail to eliminate tumors, the tumors grow.
Recently, it has been reported that indoleamine 2,3-dioxygenase (IDO), a tryptophan-metabolizing enzyme, inhibits the proliferation of T cells and NK cells and activates regulatory T cells, thereby causing the depression of the host immune system. The expression of IDO is increased in the tumor tissue, and IFN-γ stimulation induces expression of IDO in cancer cells and dendritic cells (for example, the Journal of Clinical Investigation (J. Clin. Invest.), vol. 117, No. 5, pp. 1147-1154 (2007)). In a human, in the kynurenine pathway, in which IDO is involved as the initiation step, 90% of tryptophan, an essential amino acid, is metabolized into kynurenine, and subsequently into 3OH-kynurenine, quinolinic acid, and the like. Activation of IDO decreases the tryptophan concentration and increases the kynurenine concentration in a local or systemic manner, and tryptophan metabolites containing kynurenine induce the death of T cells and NK cells (for example, the Journal of Experimental Medicine (J. Exp. Med.), vol. 196, No. 4, pp. 447-457 (2002)). The tryptophan metabolism induces conversion of CD4+CD25− T cells into regulatory T cells (for example, Blood, vol. 109, No. 7, pp. 2871-2877 (2007)). In the culture supernatant of dendritic cells in which expression of IDO has been induced by INF-γ, the tryptophan concentration is decreased and the kynurenine concentration is increased. In co-culture of T cells with such dendritic cells, T cell proliferation is suppressed compared to co-culture with unstimulated dendritic cells (for example, the Journal of Experimental Medicine (J. Exp. Med.), vol. 196, No. 4, pp. 447-457 (2002)).
From the above facts, in the tumor environment with an increased expression of IDO, the increased kynurenine concentration induced by tryptophan metabolism suppresses antitumor effector cells, which is considered to be one of the immune escape mechanisms in tumors (for example, the Journal of Clinical Investigation (J. Clin. Invest.), vol. 117, No. 5, pp. 1147-1154 (2007)).
An increased expression of IDO in the tumor tissue of colorectal cancer and prostate cancer has been reported (for example, Clinical Cancer Research (Clin. Cancer Res.), vol. 12, No. 4, pp. 1144-1151 (2006); and European Journal of Cancer (Eur. J. Cancer), vol. 44, No. 15, pp. 2266-2275 (2008)). In acute myeloid leukemia cells, IDO is constitutively expressed (for example, Leukemia, vol. 21, pp. 353-355 (2007)). It is reported that endometrial cancer, melanoma and ovarian cancer patients with an increased expression of IDO have a poor prognosis (for example, British Journal of Cancer (Br. J. Cancer), vol. 95, No. 11, 1555-1561 (2006); the Journal of Clinical Investigation (J. Clin. Invest.), vol. 114, No. 2, 280-290 (2004); and Clinical Cancer Research (Clin. Cancer Res.), vol. 11, No. 16, 6030-6039 (2005)). In adult T cell leukemia lymphoma and acute myeloid leukemia, the kynurenine/tryptophan ratio in the blood is increased (for example, Leukemia Research (Leuk. Res.), vol. 33, No. 1, pp. 39-45 (2009); and Leukemia Research (Leuk. Res.), vol. 33, No. 3, pp. 490-494 (2009)). It is reported that melanoma patients with an increased kynurenine/tryptophan ratio in the blood have a poor prognosis (for example, Dermatology, vol. 214, No. 1, pp. 8-14 (2007)). As mentioned above, it is thought that IDO and/or kynurenine is involved in many solid cancers and blood cancers.
1-methyltryptophan (1-MT), a tryptophan derivative, competes with tryptophan and thereby inhibits kynurenine production (for example, Cancer Research (Cancer Res.), vol. 67, No. 2, pp. 792-800 (2007)). Suppression of T cell proliferation in the presence of IDO-expressing cancer cells and dendritic cells is cancelled by 1-MT (for example, Cancer Research (Cancer Res.), vol. 67, No. 2, pp. 792-800 (2007)). Further, 1-MT induces major histocompatibility complex (MHC)-restricted rejection in allogeneic pregnant mice (for example, Nature Immunology (Nat. Immunol.), vol. 2, No. 1, pp. 64-68 (2001)). These results suggest that inhibition of IDO suppresses kynurenine production and induces immunity.
In mice bearing mouse melanoma cells, 1-MT shows an antitumor effect. This effect disappears in immunodeficient mice (for example, Cancer Research (Cancer Res.), vol. 67, No. 2, pp. 792-800 (2007)). These results suggest that the antitumor effect of 1-MT is based on immunostimulation caused by IDO inhibition-mediated inhibitory effect on kynurenine production.
On the other hand, it is reported that, in HIV positive patients, the IDO expression in PBMC and the viral load correlate with each other (for example, Blood, vol. 109, pp. 3351-3359 (2007)). It is also reported that, in chronic hepatitis C patients, the IDO mRNA level in the liver is increased, and the kynurenine/tryptophan ratio in the serum is increased (for example, the Journal of Virology (J. Virol.), vol. 81, No. 7, pp. 3662-3666 (2007)).
As mentioned above, it is thought that IDO inhibitors and/or kynurenine production inhibitors are promising as a preventive or therapeutic agent for diseases in which kynurenine production is involved, such as cancer, AIDS, AIDS dementia, Alzheimer's disease, depression, infections, and immune diseases.
On the other hand, pyrazine derivatives having an endothelin antagonistic effect are known (see patent literature 1 and nonpatent literature 1).
As a therapeutic agent for diseases in which chemokines are involved, N-pyrazinyl-2-thiophenesulfonamide derivatives (see patent literature 2), N-pyrazinylbenzenesulfonamide derivatives (see patent literature 3) N-(2-quinoxalinyl)benzenesulfonamide derivatives (see patent literature 4), and the like are known. As a chemokine receptor antagonist, N-pyrazinylbenzenesulfonamide derivatives, N-(2-quinoxalinyl)benzenesulfonamide derivatives (see patent literatures 5 and 6), pyridopyrazin-2-on-3-ylmethanesulfonamide derivatives (see patent literature 7), and the like are known. As a functional modulator of thymus and activation-regulated chemokine (TARC; CC chemokine ligand 17 (CCL17)) and/or of macrophage-derived chemokine (MDC; CC chemokine ligand 22 (CCL22)), N-pyrazinylbenzenesulfonamide derivatives, N-(2-pyridopyrazinyl)benzenesulfonamide derivatives (see patent literature 8), and the like are known.
N-(2-quinoxalinyl)benzenesulfonamide derivatives (see patent literatures 9 and 10) having an inhibitory activity against phosphatidylinositol-3-kinase (PI3K), and the like are known.